From Educated Guess to AcceptedPractice: The Use of OralAntidiabetic Agents in Pregnancy

ODED LANGER, MD, PhD

Department of Obstetrics and Gynecology, St Luke’s-Roosevelt HospitalCenter, Columbia University, New York, New York

Abstract: When pharmacologic therapy is required,oral antidiabetic agents have been almost universallyendorsed as first line drugs in the treatment of gesta-tional diabetes mellitus (GDM) based on well-designed studies that have found no association be-tween these agents and congenital malformations.These agents have an efficacy comparable with insulinin their ability to facilitate achievement of targetedlevels of glycemic control on all GDM severity levelsand in obese patients. Therefore, level of glycemiccontrol achieved, not the mode of therapy is the keyto improving outcomes in GDM.Key words: gestational diabetes, glyburide, level ofglycemic control, perinatal outcome

Nearly 3% to 10%of the 4.5million pregnanciesannually in the United States are affected bygestational diabetes mellitus (GDM). Pharma-cologic therapy will be required in 20% to 60%of these pregnancies to maintain targeted levelsof glycemic control. Insulin has traditionallybeen considered the gold standard for the man-agement of GDM based on its effectiveness(50% to 80%) in achieving established levels ofglucose control. Antidiabetic oral agents wouldhave to provide comparable results to be con-sidered efficacious alternatives.

Oral antidiabetic agents are commonly pre-scribed for nonpregnant type 2 diabetic patients.The main objection to their use in pregnancy isthe risk for the development of congenitalanomalies,1 fetal compromise, and fetal hypo-glycemic episodes through direct stimulation of

the fetal pancreas.2 The historic ban on the use oforal antidiabetic agents in pregnancy has beenbased on scant evidence of case reports andone study in particular on fetal anomalies in50 poorly controlled diabetic women beforepregnancy.1

In 2000, the results of a randomized study3

comparing glyburide and insulin use in preg-nancy demonstrated similar outcomes and theability to achieve established levels of glucosewith either drug. The results of this study helpedto swing the pendulum toward acceptance ofglyburide in the treatment of GDM. Treatmentapproval, reflected in editorials, clinical opi-nions and follow-up studies with comparableresults, was followed by endorsements for itsuse by the North American Diabetes in Preg-nancy Study Group (2002)4 and in 2005 by theFifth International Workshop on GestationalDiabetes (sponsored by the American DiabetesAssociation).5–10

Thus today, the use of oral antidiabetic drugs,especially glyburide, has become the standard ofcare in the management of gestational diabetesinmany centers and in private practices through-out the United States. Of note, oral antidiabeticagents were used in the United Kingdom andSouth Africa in the early 1960s but with adisregard for rigid evidence-based standards(grossly underpowered, flaws in design andconduct, and first generation antidiabetic druguse rarely prescribed today). Ironically today, inlight of the overwhelming evidence that has beencollected from basic science studies addressingpharmacologic characteristics of these drugs inrandomized and case-controlled studies, practi-tioners in Europe show a reluctance to use thedrugs!

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Correspondence: Oded Langer,MD, PhD, Departmentof Obstetrics and Gynecology, St. Luke’s-RooseveltHospital Center, 1000 Tenth Avenue, New York, NY10019. E-mail: odlanger@chpnet.org

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 50 / NUMBER 4 / DECEMBER 2007

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 50, Number 4, 959–971r 2007, Lippincott Williams & Wilkins

This review provides the rationale for the useof oral antidiabetic agents in pregnancy as anefficacious alternative to insulin. It describeshow research from the basic sciences (placentaltransfer) to clinical studies (perinatal outcome)have lead to significant evidence on which tobase management recommendations for the useof these drugs in the treatment ofGDMand type2 diabetes. The association between level ofglycemic control, treatment modalities, diseaseseverity, and obesity are evaluated.

The Foundation for the Use of OralAntidiabetic Agents in theManagement of GDMNormal pregnancy is generally characterized byperipheral insulin resistance, which causes anincrease in b-cell activity (insulin secretion).The result will be an approximate 50% decreasein insulin-mediated glucose disposal and a 200%to 250% increase in insulin secretion. The basicmetabolic defect in women with GDM suggeststhe limited capacity of pancreatic b-cells toincrease insulin secretion to compensate for theenhanced insulin resistance of pregnancy (im-pairment in the first phase of insulin secretion).11

In addition to their diminished b-cell reserve, theincreased insulin resistance found during preg-nancy has been shown to be present before andafter pregnancy.11

Insulin resistance, that is, impaired tissueresponse to insulin, occurs early in the diseaseprocess leading to type 2 diabetes.12 Insulinresistance alone, however, does not cause dia-betes. Most obese people do not develop type 2diabetes despite increased insulin resistance;there needs to be an accompanying relativeinsulin deficiency. Initially, early in the dete-rioration stages (prediabetes, GDM), the pan-creatic b-cells respond by secreting more insulinwith the increase in insulin resistance tomaintainnormal glucose tolerance (compensatory hyper-insulinemia). With the increase in insulin resis-tance, there is a decline in insulin secretion withan accompanying glucose intolerance character-ized by postprandial and/or fasting glucose ele-vation. Thus, during the prediabetes stage,glucose intolerance (GDM) and metabolic syn-drome can be identified years before the devel-opment of the threshold that defines type 2diabetes.

As b-cell function further declines, hypergly-cemia becomes more severe. Forty percent ofb-cell mass may be lost in individuals who have

glucose intolerance and approximately 60% losswhen clinical type 2 diabetes develops. Hepaticinsulin resistance and relative insulin deficiencyalso leads to an increase in hepatic gluconeogen-esis, which further worsens the degree of hyper-glycemia. Thus, prediabetes may includepatients with metabolic syndrome, gestationaldiabetes, and impaired glucose tolerance andfasting plasma glucose (FPG). All represent‘‘stations’’ on the road to type 2 diabetes.

It is well recognized that obesity and preg-nancy are factors that affect increased insulinresistance. The additional stimulation on the b-cells alone is another reason for b-cell deteriora-tion. GDM women, either lean or obese, arecharacterized by further insulin resistance andan inability to increase insulin secretion as acompensatory response. Therefore, type 2 andgestational diabetes are actually the samediseasewith different names that occur at differentstages on the glucose continuum of naturaldeterioration of glucose intolerance.13

It should be noted that type 2 diabetes isdefined on the basis of a selected threshold onthe glucose intolerance continuum. Thesethresholds are fluid, for example, in the past,the threshold required for a diagnosis of type 2diabetes was fasting of 140mg/dL, whereas cur-rently it is 126mg/dL. The thresholds were cre-ated on the basis of the rate of complicationsassociated with a particular threshold. Newresearchmay reveal the need for different thresh-olds. In summary, GDM represents an earlystage of the deterioration continuum towardtype 2 diabetes. The foundation for this concep-tual framework is based on the similarities in riskfactors and metabolic and endocrine abnormal-ities: type 2 diabetes and GDM are hetero-geneous disorders whose pathophysiology ischaracterized by peripheral insulin resistance,impaired regulation of hepatic glucose produc-tion, and declining b-cell function. Among dif-ferent ethnic groups, both forms have beendiagnosed in varying prevalence.

The b-cell function in 4209 newly diagnosedtype 2 diabetic womenwas only 51%as shown intheUnitedKingdomPerspectiveDiabetes Study(UKPDS) followed by a progressive decline toapproximately 28% after 6 years.14,15 The b-cellloss may begin more than a decade before thediagnosis and is, therefore, the consequence of adisease process that has remained undetected.Thirteen to 14 years after diagnosis, b-cell func-tion and insulin secretion may plunge to zero.16

Therefore, if oral antidiabetic agents are the goldstandard for therapy in type 2 diabetes, from

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monotherapy to combination therapy in relationto the disease severity, it is reasonable to spec-ulate that women with GDM will respond tooral therapy with even greater success. Thesepharmacologic agents should be prescribed be-cause of ease of use, noninvasive strategy, andcost-effectiveness as an alternative therapy op-tion offered to patients. However, the above canbe provided as a management alternative onlyafter there is conclusive proof of the efficacy andsafety of these drugs in comparison with othertherapies.

Will the Use of Sulfonyureas inPregnancy, Especially Glyburide,Cause an Earlier Exhaustionof b-cells in GDM Patientsin Later Life?Approximately 70% of women who experienceGDM will develop type 2 diabetes within 10years after delivery. The risk to develop type 2diabetes varies markedly in different studies andin patients of different ethnic and geographicbackgrounds.17 The UKPDS demonstrated thatinsulin deficiency was a progressive conditionthat did not appear to be affected if a patientreceived sulfonylurea or metformin therapy.14,15

The pharmacologic effect of antidiabetic agentson plasma glucose will gradually disappear afterthe drug use is discontinued, that is, ‘‘wash-out’’period. In diabetes prevention trials with pa-tients with impaired glucose tolerance, the effectof metformin, acarbose, and troglitazone beganto disappear shortly after the drugs were discon-tinued.18 In addition, the use of troglitazone inthe Prevention of Diabetes study of women withprevious GDM, reported improvement in insu-lin secretion after the wash-out period. This maybe the result of the selection of younger womenin comparison with the other studies. Similareffects were seen in our experience with GDMpatients treated with insulin therapy. When thedrug was discontinued by the patient, they re-mained within the targeted levels of glucosecontrol for 1 to 2 weeks before the wash-outeffect set in.

In summary, it is not reasonable to assumethat within the 8 to 12-week window of GDMtherapy with glyburide or any other oral anti-diabetic agents that the drug will either contri-bute to an escalation or deterioration ofpancreatic function. In fact, if this was the case,no oral therapy with sulfonylureas or sulfony-

lurealike drugs could be used in the treatment oftype 2 diabetes. Obviously, this is not the case.

Oral Agents: PharmacologicCharacteristics (Tables 1 and 2)Different oral antidiabetic agents act upon di-verse mechanisms of action to correct or im-prove the pathologic lesion responsible forglucose intolerance. Therefore, these drugs pro-vide an enhanced approach to the treatment oftype 2 and gestational diabetes (Fig. 1). Further-more, combination therapies will further im-prove the effect of these drugs on glucosemetabolism. Insulin, in contrast to the oralagents, is designed to mimic the physiologicsecretion of endogenous insulin. The basal in-sulin is supplied by the administration of inter-mediate or long acting at bedtime or beforebreakfast and at bedtime. The meal-related (glu-cose excursion) insulin includes the use of shortacting insulin.

Sulfonylureas that require functional pan-creatic b-cell for their hypoglycemic effects havebeen used to treat type 2 diabetes for manydecades. They bind to specific receptors(SUR1: sulfonylureas, repaglinide, nateglinide)on b-cell plasma membrane, resulting in closureof potassiumATP channels with a parallel open-ing of calcium channels. The resulting increase incytoplasmic calcium stimulates insulin release.The principal significance of these drugs is toimprove insulin secretion. Enhanced insulin se-cretion suppresses the production of hepaticglucose, the main contributor to fasting hyper-glycemia. It lowers glucose toxicity and facili-tates insulin secretion after meals therebyreducing postprandial hyperglycemia. Thesedrugs as a secondary effect can also improveperipheral tissue sensitivity to insulin as shownby several studies.19–21

The peak plasma level of glyburide (known asglibenclamide in Europe) when given as a singleagent occurs within 4 hours and its absorption isnot affected by food intake. Glyburide is exten-sivelymetabolized in the liver and itsmetabolitesare extracted in bile and urine to equal extent.Six metabolites of glyburide are formed by thehuman and baboon placentas and livers but therates of their formation are different betweenorgans and species.22 The half-life of glyburide isapproximately 10 hours and results in elimina-tion and a steady-state time of (1/2 life-time � 5)50 hours. This component needs to be addressedbecause there is frequent dose adjustment (in all

From Educated Guess to Accepted Practice 961

oral agents). The starting dose is 2.5mg orally inthe morning. If the targeted level of glycemia isnot attained, add 2.5mg to the morning dose. Ifindicated (after 3 to 7 d), add 5mg in the evening.Thereafter, increase the dose by 5-mg incre-ments, up to a total of 20mg/d. If the patientdoes not achieve targeted levels of glycemiccontrol, add long-acting insulin to the regimenor assign the patient to insulin therapy alone(Fig. 2).

Hypoglycemia is the main side effect of gly-buride therapy and is dose-related. It may occurin 11% to 38% of nonpregnant type 2 diabeticsand is a greater risk for the older patient. Theserates are significantly lower in pregnancy be-cause prospective mothers are generally youngerand healthier.

In our original randomized study, we evalu-ated the number of hypoglycemic episodesthroughout pregnancy. We found a significantdecrease in the glyburide compared with theinsulin-treated patients.3

In another study, using continuous bloodglucose monitoring for 3 days, we reconfirmedour original findings; however, the testing timewas limited.23

Furthermore, when insulin and glyburidewere compared for weight gain in pregnancy,

no difference was noted between the groups.Although glyburide has been found to be asso-ciated with increased weight gain in nonpreg-nant type 2 (long-term) diabetes, GDM is ofrelatively short-term duration (weeks).3

BiguanidesMetformin (Glucophage) affects the glycemicprofile by improving insulin sensitivity at thecellular level (insulin sensitizer). The cellulareffects of metformin are to counteract insulinresistance and basal plasma insulin levels. Itschief glucose-lowering action suppresses hepaticglucose output by reducing the excessive rates ofglucose production, which in turn decreasesgluconeogenesis. The drug also decreases hepa-tic glycogenolysis and increases insulin-stimu-lated glucose uptake in skeletal muscles. Thisaction causes a reduction in the recognized toxicmetabolic effects of hyperglycemia (glucose toxi-city) and fatty acids (lipotoxicity) in type 2diabetes.

Its metabolic effects include reduction offatty acid oxidation; increase in splanchnic glu-cose turnover; improvement of lipid profile withthe decline of triglyceridemia, fatty acids, and

TABLE 1. Selective Characteristics of Oral Antidiabetic Agents

Class

Duration of

Antidiabetic

Action (h)

Decrease in

FPG (mg/dL)

Decrease in

Hemoglobin

A1C (%)

Half-life

Time (h) Side Effects

Sulfonylureas 60-70 1.5-2 10 Hypoglycemia, weightgain

Chlorpropamide 24-72Glipizide 24Glyburide (DiaBeta,Micronase)

12-24

Glyburide (Glynase) 24SecretagoguesRepaglinide Unknown 60-70 1.5-2 4 Hypoglycemia, weight

gainNateglinide —

BiguanidesMetformin 6-12 60-70 1.5-2 6.2 GI symptoms

ThiazolidinedionesPioglitazone >24 60-70 1.5-2 3-7 Weight gain, fluid

retentionRosiglitazone >24 3-4 GI symptoms

Glucosidase inhibitorsCarbose Unknown 35-40 0.7-1 2Miglitol Unknown 20-30 0.7-1

DPP-4 inhibitorssitagliptin

— URI nasopharyngitis,headache

FPG indicates fasting plasma glucose; GI, gastrointestinal; URI, upper respiratory infection.

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low-density lipoprotein cholesterol while tosome extent increasing high-density lipoproteincholesterol and decreasing intestinal absorptionof glucose and utilization. Metformin, too, sta-bilizes weight reduction but does not stimulateinsulin secretion. Therefore, it does not causehypoglycemia in either diabetic or control sub-jects or stimulate the fetal pancreas to oversecrete insulin.

Metformin was introduced after the withdra-wal of phenformin (a first generation biguanide).Lactic acidosis with the use of metformin isinfrequent (0.03 cases/1000 patient-years), onetenth that of phenformin. Lactic acidosis in-

creases with renal dysfunction and patient age.Its peak plasma level, given as a single agent,occurs within 4 hours. Although food intakereduces absorption, it should not be adminis-tered without it, because it can produce gastro-intestinal intolerance. Metformin is a highlywater-soluble drug that is not metabolized andis eliminated unchanged through the kidneys bytubular secretion; glyburide ismetabolized in theliver. Peak plasma concentrations are short-lived; in patients with normal renal functionthe plasma half-life (t1/2) for metformin is 2 to5 hours with almost 90% of an absorbed dosageeliminated within 12 hours.24 Renal clearance of

TABLE 2. Oral Antidiabetic Drugs Pharmacologic Effects

Drug Mechanism of Action

Pregnancy

Category

Cross

Placenta

Excreted

in Breast

Milk Daily Maintenance Dosage

Sulfonylureas Increase insulin secretion

Glimepiride

(Amaryl)

C Unknown Unknown 1-8mg/d as a single daily dose

with breakfast or the first main

meal of the day

Glipizide

(Glucotrol)

C Minimal Unknown 5-40mg/d as a single daily dose 30min

before breakfast

Glipizide-

GITS

(Glucotrol

XL)

— — — 5-20mg/d as a single dose

with breakfast

Glyburide

(DiaBeta,

Glynase,

Micronase)

B No No 0.75-12mg/d as a single daily

dose with breakfast or the first

main meal or as 2 divided doses

Meglitinides Increase insulin secretion

Nateglinide

(Starlix)

C Unknown Unknown —

Repaglinide

(Prandin)

C Unknown Unknown 1-16mg/d in 2 to 4 divided

doses within 15-30min before meals

Biguanide Decreases hepatic

Metformin

(Glucophage)

Gluconeogenesis, increase

insulin sensitivity

B Yes No 1500-2550mg/d in 2 or 3

divided doses with meals

Glitazones Increased insulin

sensitivity, decrease

hepatic glucose

production

Pioglitazone

(Actos)

C Unknown Animals 15-45mg/d as a single daily

dose (with or without meals)

Rosiglitazone

(Avandia)

C Unknown Animals 4-8mg/d as a single daily dose or in 2

divided doses in the morning and

evening (with or without meals)

a-Glucosidase

inhibitors

Slow absorption of

carbohydrates in the

intestine

Acarbose

(Precose)

B Unknown Animals 150-300mg/d in 3 divided doses

at the start of each day

Miglitol

(Glyset)

B Unknown Animals 150-300mg/d in 3 divided doses

at the start of each meal

From Educated Guess to Accepted Practice 963

metformin occurs more often by tubular secre-tion than glomerular filtration with minimalbinding of metformin to plasma proteins. Onthe other hand, glyburide is cleared by the liverand kidneys with 99.8% bound to plasma pro-teins. As a result, with the use of metforminin pregnancy, its therapeutic level should be

adjusted with the method of clearance becauseof the increased glomerular filtration rate inpregnancy. Metformin should be introducedgradually in 500-mg or 850-mg increments to amaximum effective dose of 2000mg/daily. Theabsolute maximum dose is 2550 or 3000mg/d.Metformin is contraindicated in the presence of

muscleuptake of glucose

muscleuptake of glucose

InsulinsecretionInsulin

secretion

HyperglycemiaHyperglycemia

hepaticglucose production

hepaticglucose production

Sulfonylureas (+)Megalitinides & analogs (+)(repaglinide)Exenatide (byetta) (+)

Thiazolidinediones (-)Biguanides (metformin) (-)

Glyburide (-)

Thiazolidinediones (+)Biguanides (metformin)(+)

FIGURE 1. Oral antidiabetic agent: mechanism of action.

Gestational or Type 2 Diabetes

Postprandial blood glucose Levels of 120 to 180 mg/dL (6.7 to 9.4 mmol/L)

OrFasting blood glucose of 95 to 140 mg/dL

(5.3 to 7.8 mmol/L)

Glyburide

Combination Therapy

Glyburide + MetforminGlyburide & Acrabose

Glyburide + Insulin (pm)

Insulin

Dose and Adjustment1. 2.5 mg, morning2. Increase by 2.5 mg first week3. Add evening 5 mg4. Increase AM 5 mg5. Increase PM 5mg

Maximum: 20 mg/d

FIGURE 2. Algorithm of drug administration and decision-making.

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renal disease. Clinical trials in 2 centers exam-ined the effect of metformin as single therapy innonpregnant obese subjects with type 2 diabetesand in poorly controlled sulfonylurea-treatedsubjects. In both studies, the mean decline inplasma glucose concentration was about 60mg/dL and there were observed beneficial effects onplasma lipid levels.15,25

ThiazolidinedionesThiazolidinediones are category C drugs thatshould only be prescribed in pregnancy if thelikely benefit justifies the potential risk to thefetus. These drugs should be used cautiouslywith confirmation of liver disease or abnormalliver testing (alanine aminotransferase levels>2.5 times the upper limit for the laboratory),and in patients compromised with heart diseaseor a history of heart failure. Liver function needsto be measured before initiation of therapy andbimonthly during the first year of treatment.There is evidence of substantial weight gain withthe use of both drugs. There is scant evidenceof these contraindications in pregnancy and,therefore, most patients should be able to usethe drug.

a-Glucosidase InhibitorsThis group of drugs slows the absorption ofcarbohydrates in the intestines thereby reducingthe postprandial rise in blood glucose.26 Becauseof gastrointestinal side effects with the use ofthese drugs, gradual dosage increments, overweeks tomonths is recommended after initiationof therapy. Acarbose (Precose), miglitol (Gly-set), and voglibose, currently in clinical use, maybe added to most other available therapies.

The use of these drugs in pregnancy is limited(100 patients to date) despite the fact that theaction of acarbose is within the gastrointestinaltract and is not transferred by the blood streamto the placenta. However, it is less effective thanglyburide in decreasing glucose levels to thoserequired in pregnancy. Recently, in a small-scalestudy of 59 patients of which 29 were rando-mized to acarbose therapy and 30 to placebo, thesuccess rate with acarbose was 58% with asignificantly lower weight gain when comparedwith the placebo group. The study was under-powered to evaluate any outcome variables.17,27

Its primary use in pregnancy should not be asmonotherapy but rather in combination withglyburide and possibly metformin.

Solving the Placental TransferEnigma of Oral Antidiabetic AgentsFetal anomalies, macrosomia, and neonatalhypoglycemia have all been attributed to theuse of these drugs without inclusion of dataexplaining failure to achieve established levelsof glycemic control. Moreover, these assump-tions have not been confirmed by specific corre-lationwith the degree ofmaternal-fetal placentaltransfer of these drugs. There have been 3 mainconcerns against the use of oral hypoglycemicagents in pregnancy on the basis of clinicalobservations mostly in the 1960 to 1970s, and1980s primarily in type 2 diabetes using firstgeneration sulfonylurea drugs: (1) increased rateof congenital anomalies,1 (2) the potential forfetal macrosomia caused by direct stimulation ofthe fetal pancreas resulting in hyperinsulinemia,and (3) the increased rate of hypoglycemia owingto fetal hyperinsulinemia. These potential nega-tive effects were cited in a single case report of 3infants whose mothers received chlorpropamideand another mother of an infant given acetohex-amide, with another case report describing pro-longed symptomatic neonatal hypoglycemia.2

The recirculating single-cotyledon human pla-cental model is widely used to characterize thetransport andmetabolismofnumerous drugs andnutrients. It has been recognized as a safe in vitrosurrogate for human placental transfer. It is apractical model because it facilitates the study ofintact human placenta independent of fetalmetabolism. Finally, each experiment can bevalidated with the addition of antipyrine as areference point for the level of transfer.

With this in mind, we sought to evaluate ifsulfonylurea drugs readily cross the placenta.We used a recirculating single-cotyledon placen-tamodel in vitro to characterize thematernal-to-fetal term placentas perfused immediately afterdelivery. As glyburide has a molecular weight of494 units, it is one of the largest oral hypogly-cemic agents and also the most commonly usedsecond-generation sulfonylurea. Peak serum le-vels after a single oral dose of 5mg occur at 4hours and range from 112 to 360 ng/mL. Over99.8% of glyburide is extensively bounded toalbumin and metabolism occurs through hydro-xylation in the liver to inactive metabolism ofglyburide across the human placenta. We de-monstrated28–30 that second-generation oral hy-poglycemic agents, especially glyburide, do notsignificantly cross the diabetic or nondiabeticplacenta. Fetal concentrations reached no morethan 1% to 2% of maternal concentrations.These findings were supported by our clinical

From Educated Guess to Accepted Practice 965

study3 in which glyburide was not detected inumbilical artery blood or showed increased fetalinsulin levels. Furthermore, we sought to ruleout the possibility that the time from adminis-tration of the drug to the mother may affect thefindings in the fetus. In 13 mothers who receivedthe drug shortly before delivery, glyburide dosewas within therapeutic concentrations rangingfrom 50 to 150 ng/mL, whereas arterial cordblood levels of glyburide were undetectablewith high-performance liquid chromatographicanalysis.

Koren31 in analyzing the results of our studiessuggested a pharmaco-physiologic alternativeexplanation for glyburide’s lack of transferabil-ity across the placenta by using the classic factorsaffecting placental permeation. The author ad-vocated for plasma protein binding as the ex-planation for glyburide’s lack of transferabilityacross the placenta. Tolbutamide, chlorpropa-mine, and glipizide have high protein binding(>96), with glyburide’s protein binding of99.8%. This results in a 4% circulating tolbuta-mide versus 0.2% circulating glyburide (20-foldmore molecules available to cross the placenta).Another unique feature of glyburide is that theprotein binding is stable at serum concentrationsexceeding 10-fold levels encountered during clin-ical use. The short lifetime of glyburide (4 h) andits rapid clearance rate (1.3±0.5mL/kg/min)also contribute to the lack of transferability.

A potential problem is that albumin levelsdecrease physiologically in pregnancy owing toan increase in glomerular filtration rate. Thus,there is increased transfer of glyburide. How-ever, when this hypothesis was tested, it wasshown that decreased albumin concentrationassociated with pregnancy is unlikely to affectthe deposition of glyburide.32 In addition, it wasdemonstrated in perfusion studies that glyburideis actively effluxed by a transporter other thanP-glycoprotein. Alternatively, it is possible thata smaller portion of glyburide is carried byP-glycoprotein or, that most of the fetal load ispumped to the mother by an as yet unidentifiedplacental transport system.33 Recently, Gedeonet al34 demonstrated that glyburide is trans-ported by BCRP and MRP3. It was also foundto be an inhibitor of BCRP, PGP, MRP1,MRP2, and MRP3. The elimination of thethreat of glyburide crossing the placenta andthe adverse affects to the fetus (malformationsand hypoglycemia) enhances the potential forthe use of glyburide as a vigorous alternativepharmacologic agent in the management ofGDM patients.35–37

The majority of drugs used in pregnancycross the placenta although very few will causeadverse fetal outcome. Company informationprovided byGlucophage, Bristol-Myers Squibb,1997, explains that there is a partial placentalbarrier to metformin. Studies of transplacentaltransport of metformin reported that it notice-ably crosses the placenta,38–39 but has minimalaffect on transplacental glucose flux.28 In addi-tion, 2 studies measured metformin levels inumbilical cord blood at delivery. In the firststudy, arterial and venous umbilical sampleswere not analyzed separately and it is unclearwhether the results originate from maternal orfetal samples.40 In the second study, cord bloodsamples for metformin were taken from 15 pa-tients. The time between the last drug intakebefore sampling ranged from 4 to >48 hours.The authors concluded that metformin freelypasses the placenta and that the fetus is exposedto therapeutic concentrations. However, therewere no teratogenic effects identified in thissmall sample-size study.41

Finally, metformin transfer into human milkis minimal. The infant concentration duringbreast feeding is <0.4% of the maternal con-centration, corrected for body weight. This issubstantially lower than the arbitrary cutoff of10% used to guide lactating mothers. Thus, thisfinding implies safety; metformin is not contra-indicated in lactating patients.42,43

The results of reproduction studies in rats andrabbits remain controversial.

One study demonstrated no teratogenicity atdoses up to 600mg/kg/d, approximately twicethe maximum recommended human dose on thebasis of mg/m2. In other studies, there has beenevidence suggesting that metformin induces alow incidence of malformations in rats. In an-other study, 2-cell mouse embryos were exposedto different levels of metformin. Although lowerlevels comparable with plasma concentrationduring treatment did not affect the blastocystdevelopment rate, the highest concentration re-sulted in a marked delay in mice development.

It has been suggested in a single-cotyledon exvivo human perfusion model using 10 term pla-centas of uncomplicated pregnancy that there isminimal transfer and fetal accumulation of rosi-glitazone. Thematernal concentration perfused inthis study corresponded to plasma levels reportedfor an 8-mgoral dose.44 In contrast, another studyusing the same technique found that the transferrate of rosiglitazone is 90% of antipyrine that isused as the reference point. Thus, rosiglitazonereadily crosses the term placenta. In addition,

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placental tissue retention of rosiglitazone is lowand the drug does not affect placental tissueviability and functional parameters.45 These ob-servations need to be reconfirmed to eliminate thedisparity in the findings and duplicated on theplacentas of diabetic women. If the findings con-firm that the drug does not cross the placenta, itmay lay the groundwork for the introductionof a new drug with tremendous potential in thetreatment of GDM, metabolic syndrome, andpolycystic ovarian syndrome (PCO) womenduring pregnancy.

The Dogma of Oral HypoglycemicAgents and Fetal AnomaliesIn approaching the dilemma of fetal congenitalanomalies and their association or lack thereofto a specific pharmacologic agent, 2 basic ques-tions need to be addressed: (1) does the drugcross the placenta? and (2) if it does, is there anestablished association between the drug andfetal anomalies? It should be noted that themajority of drugs do cross the placenta but, ingeneral, few have teratogenic effects on the fetus.

The dogma that congenital anomalies areassociated with the use of oral antidiabetic drugswas perpetuated with the results of a study,demonstrating an increased rate of congenitalanomalies in 50 type 2 patients with hyperglyce-miabefore conception (HbA1c>8%).1However,it is difficult to determine if the rate of anomalieswas caused by the use of the drug or the existinghyperglycemia. Notelowitz’46 randomized studyin 1971 of patients treated with first generationsulfonylureas and insulin resulted in only 2 birthswith anomalies. One infant treated with tolbuta-mide had choanal atresia and the other treatedwith insulin had Fallot syndrome. His conclusionwas that sulfonylureas were safe for use in preg-nancy.46 Three studies in the 1990s also found noassociation between oral antidiabetic agents andcongenital malformations. Towner et al47 treated332 type 2 patientswithoral antidiabetic agents orinsulin before pregnancy. The authors showed, byusing a stepwise logistic regression, that mode oftherapy did not have an adverse significant effect;however, level of glycemia and maternal age weresignificant factors contributing to the rate ofanomalies.We48 found similar findings in a retro-spective analysis of 347 type 2 diabetic womenexposed to different oral antidiabetic agents, in-sulin, and diet therapy before and during the firsttrimester of pregnancy. Again, it was the bloodglucose and not the mode of therapy that had the

net effect on the rateof anomalies. Finally,Gilbertet al49 performed a systematic review and meta-analysis of 8 studies from 1996 to 2004. Theprincipal outcome measure was major malforma-tions after metformin use for polycystic syn-drome. Treatment with metformin in the firsttrimester was associated with a statistically sig-nificant 57% protection effect with an anomalyrate of 1.7% in the metformin group comparedwith 7.2% in a matched control group. Theauthors concluded that there is no evidence ofan increased risk for major malformations withmetformin use during the first trimester.

Two other studies reported the use of metfor-min in women with PCO syndrome. Glueck etal’s50 study suggested that metformin is safe anduseful in the reduction of GDM in women withPCO. They evaluated 33 nondiabetic womenwith PCO who were treated with metforminprospectively and 39 nondiabetic women nottreated with metformin evaluated retrospec-tively. The development of GDM was 3% inthe former and 23% in the latter. In the study byJakubwicz et al,51 the authors sought to investi-gate the effect of preconceptual use ofmetforminon early pregnancy loss by evaluating 65 womenwith PCO receiving metformin compared with31 women untreated with the drug. The earlypregnancy loss in the former was 11% and 58%in the untreated group. All 62 infants in themetformin-treated group were normal with theexception of 1 infantwho had chondrodysplasia.The data in both studies suggest that the use ofmetformin preconception and during the firsttrimester is not associated with major fetal mal-formations or fetal hypoglycemia after birth. Todate, the cumulative available evidence suggeststhat the cause of anomalies in diabetes in preg-nancy is the failure to achieve the establishedlevel of glycemic control and not the use of oralantidiabetic drugs, especially since replacementby the second generation of hypoglycemic drugs.

Should Type 2 and PCO PatientsTreated With MetforminPreconception Remain on theMedication Throughout Pregnancy?Although metformin crosses the placenta, it is aclass B drug. It may be a potentially attractivealternative to insulin in the management ofGDMpatients because its pharmacologic actionreduces hepatic glucose production and insulinresistance, However, until such time that a well-controlled study will be conducted in type 2 and

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GDM patients, metformin use should not beendorsed. We are currently awaiting the resultsof an ongoing randomized trial adequately pow-ered addressing the possible effect of metforminin pregnancy (MiG study-Metformin in Gesta-tional Diabetes).

Can targeted levels of glycemic control beachieved in type 2 diabetic pregnant patients?The targeted level of glycemic control in non-pregnant patients is <150mg/dL to preventmacro and microcardiovascular complications.In pregnancy, the desired level of glycemic con-trol to prevent perinatal complications such asfetal macrosomia, stillbirth, metabolic, respira-tory, and hematologic complications is muchlower. It is reported to be <100mg/dL and/or<120mg/dL postprandial determinations.53,54

Glyburide, metformin, and the majority ofother oral antidiabetic drugs reduce FPG by 2 to4mmol/L accompanied by a decrease in HbA1cof 1% to 2% (a decrease of 1%=20 to 30-mgglucose). Therefore, type 2 diabetic patients whocommonly reach higher plasma glucose levels(HbA1c >10%) may not be able to achieve thetargeted levels of control with oral antidiabeticagents in pregnancy. To date, there is paucity ofdata on the use of these drugs in pregnancy incomparison with insulin therapy. One can spec-ulate that type 2 diabetic patients in phase 1 ofthe disease (early onset)may benefit frommono-therapy or combination or oral antidiabeticdrugs, that is, glyburide and metformin. Moreseverely ill type 2 diabetic pregnant women(phases 2 and 3) will most likely fail to achievedesired levels of glycemic control with oral anti-diabetic agents.

The Association Between TargetedLevels ofGlycemicControl andOralAntidiabetic Agents in theManagement of GDMThe achievement of established levels of glyce-mic control in diabetic patients, both pregnantand nonpregnant, became axiomatic as a majorfactor for improving outcome. The mainstay ofglycemic control in pregnancy has been the useof insulin therapy. The use of intensified therapyin diabetes management has become the stan-dard of care to obtain the above goal. TheUKPDS14,15,25 and the Diabetes ComplicationsClinical Trials (DCCT) strongly supported itsuse with type 1 and 2 diabetic patients to achieveand maintain near normal HbA1c and to deterdiabetic complications.

A major finding in the UKPDS was that type2 diabetes is a progressive disease with increas-ingly greater b-cell deterioration that, over time,requires increased and/or multiple therapies tomaintain near normal glycemic control. In thefirst 5 years of the study, 70% of the patientstreated with glyburide achieved the desired goal.In years 3, 6, and 9, the desired goals wereachieved by fewer than 55%, 40%, and 30% ofpatients, respectively, using a single agent (in-sulin, sulfonylurea, or metformin). The authors(DCCT and UKPDS) concluded that the im-provement in glycemic control rather than aspecific therapy was the primary factor respon-sible for reduction of risk factors. These subjectsrepresent phases 2 and 3 of type 2 diabetes.16,25

Studies of pregnant diabetic women, includingourprospectiveGDMstudies,55 challengedhealthcare professionals to implement standards forimproved glycemic control to decrease diseasecomplications. Despite the success of intensifiedtherapy with insulin to control blood glucoselevels, a less invasive, more patient friendly alter-native that enhances patient compliance whileachieving similar perinatal outcome has becomea welcome alternative. As GDM is characterizedby a milder glycemic profile and occurs 2 to 10years earlier than type 2 diabetes, the use of oralantidiabetic agents with GDM patients shouldprove to be even more effective than its use withtype 2 diabetes.Moreover, it will be reasonable toassume that the success rate of therapy for GDMshould be at least 70% or higher than wasachieved in the UKPDS.

In our randomized study3 that comparedglyburide and insulin therapies, the goals oftreatment were to achieve mean blood glucoseof 90 to 105mg/dL, fasting blood glucose 60to 90mg/dL, preprandial concentration 80 to95mg/dL, and postprandial concentration<120mg/dL. We demonstrated that glyburideuse in GDM patients is as effective as insulinwhen 82% of the glyburide and 88% of theinsulin patients achieved the targeted levels ofcontrol. There were 8 glyburide-treated women(4%) receiving the maximal dose who failed toachieve the established levels of glycemia; theywere reassigned to insulin therapy.

In the early 1970s, in another randomizedstudy, it was shown that 80% of patients treatedwith first generation sulfonylurea: tolbutamide,chlorpropamine, and/or diet were able to main-tain their blood glucose within the targeted levelsof glycemia (<150mg/dL). In contrast, only 38%of the insulin patients were able to achieve thislevel probably because of poor compliance.46

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The glycemic threshold assigned to a givenstudy will determine the rate of success. In addi-tion, the number of samples and time-relatedglucose observations, that is, preprandial orpostprandial, may all mask and influence therelation between pregnancy outcome and levelof glycemic control. In general, with reportedresults of high morbidity rates in macrosomia orlarge for gestational age (LGA), questionsshould be raised if the targeted levels of glucosehave truly been achieved or properly defined.

Clinical StudiesSulfonylureas (glyburide) are currently the onlyoral agent group studied extensively in GDMwomen that have provided conclusive evidencefor the efficacious and safe treatment of GDM.Glyburide and metformin were found to be aseffective as insulin in maintaining desiredglycemic levels and result in comparable out-comes.3,52 However, other oral antidiabeticagents may in the future prove to have an evengreater therapeutic effect in controlling theabnormal levels of glycemia.

We3 conducted a randomized clinical trialwith 404 women comparing glyburide andinsulin-treated patients. The 2 groups did notdiffer significantly in the rates of preeclampsia,cesarean section, and level of glycemia prior andsubsequent to treatment. Additionally, no signif-icant difference was found in the overall rates ofsmall-for-gestational age, macrosomia, PonderalIndex, and the rate of perinatal complicationsbetween the groups. There was no identifiable

trend for oneof the groupswhenallwere found tobe nonsignificant. Furthermore, the 95% confi-dence interval for the difference of the mean wasfound to be relatively small, which suggests theunlikely possibility of beta errors.

When patients were stratified by level ofglycemic control to evaluate the impact of gly-cemia on the rate of abnormal fetal size, nodifference was found between the 2 treatmentgroups but there was a significantly higher rateof large infants in the poor glycemic category(Fig. 3). The results obtained in our randomizedstudy were similar to the results obtained in ourquasirandomized intensified treatment study.55

Since our original publication in 2000, severalinvestigators reported their clinical experiencewith glyburide.56–65 Each demonstrated theeffectiveness of glyburide therapy to achieve gly-cemic control. However, different studies useddifferent criteria to define success rate. Forexample, Chmait et al60 in 46 patients evaluatedfailure of glyburide therapy. Failure was definedwhen the maximum glyburide dose could notmaintain fasting plasma <110mg/dL and 1-hour postprandial<140mg/dL.Approximately81% of the patients achieved these goals. Jacob-son et al64 with 122 women on insulin and 137treated with glyburide instructed patients to testblood glucose 4/daily: fasting and either 1 or 2hours postprandials (per individual providerpreference). Targeted goals were fasting 100mg/dL, 1-hour 155mg/dL, and 2-hour 130mg/dL.Eighty-six percent of glyburide and 63% of in-sulin patients achieved these goals. However, thereported macrosomia rate was 25%.

Mean 96Mean 96 ++ 88

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FIGURE 3. The association between level of glycemic con-trol and rate of large infants by treatmentmodalities (A, goodglycemic control and B, poor glycemic control). Modifiedfrom Semin Perinatol. 2002;26:215–224.

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Several studies have sought to identify thepredictors of glyburide failure therapy. Rochonet al66 studied 101 GDM women requiringpharmacologic therapy while testing 4/daily.Criteria for success was achieving fasting be-tween 60 and 90mg/dL and 2-hour postprandial<120mg/dL. Seventy-nine percent of the wo-men achieved targeted levels of glycemic control.The authors concluded thaty ‘‘predicting gly-buride failure is difficult, but failure does notappear to be associated with increased adversepregnancy outcomes.’’ However, in this study,pregnancy outcome included shoulder dystocia10%, macrosomia (in the success group) 16%,and cesarean delivery approximately 40%.These outcome rates are higher than expectedin well-controlled diabetic women.

Kahn et al63 analyzed 95 GDMs receivingglyburide therapy. The overall success rate was81%. Criteria for failure were 20% of fastingblood glucose determinations at Z95mg/dLand 1-hour postprandial Z140mg/dL. Patientswere instructed to take the glyburide 30 minutesbefore breakfast and dinnerwhen the initial dosewas individualized on the basis of patient weightand degree of hyperglycemia. This administra-tion criterion is unconventional and deviatesfrom standard recommendations in the litera-ture. The perinatal outcome was associated with27% LGA infants and 12% preeclampsia. Theirconclusion was that ‘‘glyburide was more likelyto fail in women diagnosed in pregnancy of olderage, multiparity, with higher fasting glucosey’’Is it possible that with the above perinatal out-comes, the majority of patients were undiag-nosed type 2 diabetic women?

Recently, we sought to identify predictors oftreatment failure in GDM in 379 glyburide-treated women. Failure of glyburide therapy islargely dependent on the physician’s ability torecognize and adequately adjust the glyburidedose. Physician intervention can precludean avoidable failure. GDM severity, obesity,early gestational age at diagnosis, maternalage, and parity are all known factors thatinfluence the success rate in the treatment ofthe diabetic patient independent of pharmaco-logic agent. All of these were found to benoncontributing variables to failure rate ofglyburide therapy.67

Success in truly achieving level of glycemiccontrol may vary from study-to-study becauseof different criteria for success, failure to admin-istrate the maximal dose, different doses andadministration algorithms, length of therapy,type of patient (severity, ethnicity, and obesity),

and comparable groups (compliant vs. noncom-pliant subjects). Thus studies reporting similar‘‘success rates’’ may result in significantly differ-ent perinatal outcomes. which in turnmay lead toerroneous conclusions on cause and causation.

What remains unanswered is: will glyburidebe as effective as insulin at all severity levels ofGDM? And, is there a dose limitation abovewhich the efficacy of glyburide will decrease incomparison with insulin? We found that glybur-ide and insulin are equally efficacious for GDMtreatment at all severity levels of diabetes whenFPG on a glucose tolerance test was between 95and 139mg/dL. As the level of disease severityincreases, the success rate for achieving estab-lished levels of glycemic control decreases. Themajority of patients (71%) will require, on aver-age, up to 10mg daily dose of glyburide toachieve established levels of glycemic control.After stratifying patients by GDM severity, nosignificant difference was found in neonatal size,metabolic complications, and the compositeoutcome between the 2 treatment modalities.

For adjustment of the potential confoundingeffects of several factors, we performed logisticregression analysis when the primary outcomewas LGA. We found that the mean blood glucose[odds ratio (OR) 1.99, 95% confidence interval(CI) 1.04-3.83], severity of GDM (categorized bythe fasting plasma from the oral glucose tolerancetest) (OR2.13, 95%CI 1.09-4.18), previousmacro-somia (OR 3.73, 95% CI 1.70-8.81), and weightgain in pregnancy (OR 3.81, 95% CI 1.81-8.05)were theonly significant contributors.Again, treat-ment modality, parity, and prepregnancy weight[body mass index (BMI)] were found to be non-contributors. Therefore, reaching established levelsof glycemic control and not the mode of therapy isthe key to improving pregnancy outcome inGDMwomen.68 Obesity, in and of itself, is a precursor ofpotential adverse outcome in pregnancy.Diet-trea-ted GDM patients, overweight (BMI 26 to 29) orobese (BMI Z30), are associated with adversepregnancy outcome regardless of the level of gly-cemic control. In contrast, for those treated withinsulin therapy who achieve established glycemiclevels pregnancy, outcomewill be comparable withthose of normal weight patients.69 As glyburidetherapy has become an alternative to insulin in thetreatment of GDM, we sought to evaluate if thesuccess rate to achieve targeted levels of glycemiccontrol and perinatal outcome were comparablewith both modalities. Patients who achieved tar-geted levels of glycemic control had comparableperinatal outcome for both treatment modalities.Therefore, appropriate utilization of glyburide

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therapy in obese patients will result in pregnancyoutcome comparable with those treated with in-sulin (Fig. 4).70

In our experience, glyburide has become thedrug of choice for use in GDMwhen pharmaco-logic intervention is required, regardless ofGDM severity level and obesity. The noninva-sive, cost-effective,71 patient-friendly regimenlends itself more readily to potential patientcompliance.Although both treatmentmodalitiesshow comparable perinatal outcome, it seemsfromour and other investigators’ experience thatoral therapy ismore readily accepted than insulininjections. However, failure to achieve estab-lished levels of glycemic control, regardless ofthe choice of treatment modality and physicianfailure toprovide the appropriate drugalgorithmanddosewill result in adverse perinatal outcome.In the near future, we will require studies withappropriate sample sizes and power that willevaluate different oral antidiabetic drugs andcombination therapies, that is, glyburide andacarbose, glyburide and metformin, and also anoral antidiabetic agent in combination with in-sulin to optimize patient/physician choices in thetreatment of diabetes in pregnancy.

Note: Following is an abbreviated reference list.The complete reference list is available on line at:www.clinicalobgyn.com

References3. Langer O, Conway DL, Berkus MD, et al. A

comparison glyburide and insulin in womenwith gestational diabetes mellitus. N Engl JMed. 2000;343:1134–1138.

7. Greene MF. Oral hypoglycemic drugs for ge-stational diabetes [editorial]. N Engl J Med.2000;343:1178–1179.

9. Saade G. Gestational diabetes mellitus: a pill ora shot? [editorial]. Obstet Gynecol. 2005;105:456–457.

23. Yogev Y, Ben-Haroush A, Chen R, et al.Undiagnosed asymptomatic hypoglycemia: diet,insulin, and glyburide for gestational diabeticpregnancy. Obstet Gynecol. 2004;104:88–93.

33.Kraemer J, Klein J, LubetskyA, et al. Perfusionstudies of glyburide transfer across the humanplacenta: implications for fetal safety. Am JObstet Gynecol. 2006;195:270–274.

50. Glueck CJ, Wang P, Kobayashi S, et al. Met-formin therapy throughout pregnancy reducesthe development of gestational diabetes inwomen with polycystic ovary syndrome. FertilSteril. 2002;77:520–525.

59.KremerCJ,Duff P.Glyburide for the treatmentof gestational diabetes. Am J Obstet Gynecol.2004;190:1438–1439.

63. Kahn BF, Davies JK, Lynch AM, et al. Pre-dictors of glyburide failure in the treatment ofgestational diabetes.Obstet Gynecol. 2006;107:1303–1309.

64. Jacobson GF, Ramos G, Ching J, et al. Com-parison of glyburide and insulin for the man-agement of gestational diabetes in a largemanaged care organization. Am J ObstetGynecol. 2005;193:118–124.

67. Langer O, Most O, Monga S. Glyburide:predictors of treatment failure in gestationaldiabetes [abstract]. Am J Obstet Gynecol.2006;195:S136.

68. Langer O, Yogev Y, Xenakis E, et al. Insulinand glyburide therapy: dosage, severity level ofgestational diabetes, and pregnancy outcome.Am J Obstet Gynecol. 2005;192:134–139.

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FIGURE 4. The relationship between treatment modalities(diet, insulin, and glyburide) and perinatal outcome in well-controlled obese patient.

From Educated Guess to Accepted Practice 971